Herpes simplex viruses (HSVs) cause human diseases, including cold sores, eye and genital infections, neonatal infections and encephalitis. HSVl and HSV2 establish lifelong latent infections within sensory ganglia and recurrent infections are common. Many people in the U.S. and worldwide are infected by one or both serotypes of HSV and there is increasing evidence that HSV2 infections contribute to the spread of HIV. HSV remains a major human pathogen worldwide, causing cold sores, eye and genital infections, blindness, encephalitis, and neonatal infections. After infection, glycoproteins are expressed on the cellular membranes and are major targets ofthe host's immune response. The virus envelope contains eleven glycoproteins that are important for infection and pathogenesis. Our long term objective is to understand the mechanisms by which HSV glycoproteins interact with each other and with cell molecules to mediate HSV entry into mammalian cells. Four glycoproteins, gD, gB and a complex of gH/gL are essential for virus entry. Glycoprotein D, a structural component ofthe HSV envelope is necessary for the stable binding of the virus with receptors on cells as well as fusion ofthe virus envelope with the plasma membrane. Virus entry is triggered first by the interaction between gD and one of its receptors. This interaction then triggers downstream events that necessarily involve the core fusion machinery consisting of gB and gH/gL. An important question is: how does the interaction between gD and it(s) receptor trigger action by gB and gH/gL to cause fusion? Our approach to answering this complex question has been to study the structure and function of both the virion glycoproteins and receptors. Therefore, we propose three specific aims: 1) To further characterize gD structure and its relationship to virus entry; 2) To explore the steps of virus entry that occur after gD binds its cell receptor; and 3) To carry out structure-function studies of gH/gL of HSVl and HSV- 2. Our studies should provide information about the specific steps of HSV entry and have significance for the herpesvirus field as well as for the larger field of virus entry. On a more practical level, our findings should find application for development of vaccines and new therapeutics against HSVl and HSV2.